| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory breathlessness in patients diagnosed with chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD). |
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| E.1.1.1 | Medical condition in easily understood language |
| Breathlessness that continues despite optimal management of the underlying causes and current symptom relief measures, in patients suffering from lung disease. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether mirtazapine is an effective treatment for the reduction of self-reported worst breathlessness (as measured by a numerical rating scale (NRS)) at 56 days post start of treatment compared to placebo in patients with COPD or ILD. |
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| E.2.2 | Secondary objectives of the trial |
To assess the effectiveness of mirtazapine, compared to placebo, over time at days 7,14, 28, 56 and 180 post start of treatment on:
oWorst and average breathlessness over the past 24 hours as measured by patient reported NRS
oOther physical symptoms & on overall Quality of Life at days 28,56,180 only
oAnxiety, depression (HADS) and sense of perceived self-efficacy (GSES)
oThe consumption of opioids
oHealthcare use, in particular unplanned care
oTo evaluate safety, toxicity and tolerability of mirtazapine
To identify which patient characteristics are most associated with benefit from mirtazapine.
To assess the cost-effectiveness of mirtazapine treatment from a societal perspective versus best standard care.
To demonstrate the feasibility of delivering mirtazapine treatment across the different European countries in terms of acceptability of the offered treatment and compliance with treatment.
To evaluate the impact of patients receiving mirtazapine on caregivers.
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| The BETTER-B sub-study is the Caregiver sub-study. The aim of this sub study is to assess the caregiver burden and the experience of the participants caregivers and close family members. |
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| E.3 | Principal inclusion criteria |
1.Aged ≥ 18 years old
2.Diagnosed with:
•Chronic obstructive pulmonary disease (COPD), and/or
•Interstitial lung disease (ILD), including chronic fibrotic lung disease following SARS-CoV-2 infection
3.Breathlessness severity: Modified MRC (mMRC) breathlessness scale of:
•Grade 3 (I stop for breath after walking about 100 yards or after a few minutes on level ground) or
•Grade 4 (I am too breathless to leave the house, or I am breathless when dressing or undressing)
4.On optimal treatment of the underlying condition in the opinion of the identifying clinician (see section 9.3.3 of the protocol for guidance)
5.Management of the underlying condition unchanged for the previous 2 weeks
6.Reversible causes of breathlessness optimally treated in the opinion of the identifying clinician
7.If female, must be (as documented in patient notes):
a)postmenopausal (no menses for 12 months without an alternative medical cause), or
b)surgically sterile (hysterectomy, bilateral salpingectomy or bilateral oophorectomy), or
c)using acceptable contraception (which must be continued for 7 days after the last dose of IMP)
8.Able to complete questionnaires and trial assessments
9.Able to provide written informed consent
Caregiver eligibility:
Caregivers will be identified by an included patient participant as the person closest to them, providing the patient participant is willing for them to be approached.
Caregivers must meet all of the following criteria to be eligible:
1.Identified by an included patient as the person closest to them
2.Aged ≥18 years old
3.Able to complete questionnaires and assessments
4.Able to provide written informed consent |
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| E.4 | Principal exclusion criteria |
1.Existing antidepressant use, or other serotonergic active substances (e.g. linezolid, St John’s wort)
2.Known contraindication to mirtazapine
3.Hypersensitivity to the active substance or to any of the components of mirtazapine or placebo (e.g. lactose intolerance)
4.Australia modified Karnofsky Performance Scale ≤40
5.Pregnant or breast-feeding women. For women of childbearing potential (those not post-menopausal or surgically sterile) this must be confirmed by a pregnancy test (urine) within 7 days prior to randomisation
6.Patients with acute cardiac events within 3 months prior to randomisation (myocardial infarction, unstable angina pectoris, or significant cardiac conduction disturbance)
7.Patients with jaundice or known hepatic impairment in the opinion of the identifying clinician
8.Patients with known renal impairment in the opinion of the identifying clinician
9.Patients with uncontrolled blood pressure in the opinion of the identifying clinician
10.Patients with uncontrolled diabetes mellitus in the opinion of the identifying clinician
11.Patients with uncontrolled seizures, epilepsy or organic brain syndrome in the opinion of the identifying clinician
12.Patients with severe depression or suicidal thoughts in the opinion of the identifying clinician
13.Patients with a history of psychotic illness (schizophrenia, or other psychotic disturbances) in the opinion of the identifying clinician
14.Patients with bipolar disorder, or a history of mania or hypomania in the opinion of the identifying clinician
15.Patients currently enrolled in another interventional trial
16.Patients with known congenital QT prolongation or family history for QT prolongation.
17.Use of medicines that cause QT prolongation such as macrolides and typical antipsychotics (unless required in low-dose to relieve nausea, e.g. haloperidol ≤5mg/24h, levomepromazine ≤25mg/24h)..
18.Patients with a known history of suicide-related events
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is worst breathlessness over the last 24 hours at day 56 post start of treatment as assessed by numerical rating scale (NRS, 0=no breathlessness to 10=worst possible breathlessness). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary outcome will be evaluated when all participants have reached day 56 post start of treatment. |
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| E.5.2 | Secondary end point(s) |
•Worst breathlessness over the last 24 hours as assessed by NRS at days 7, 14, 28 and 180 post start of treatment
•Average breathlessness over the last 24 hours assessed by NRS at days 7, 14, 28, 56 and 180 post start of treatment
•Number and duration of episodes of breathlessness over the last 24 hours
•Physical and emotional aspects of breathlessness (Dyspnoea, fatigue, emotional function, mastery) as assessed by the Chronic Respiratory Questionnaire (CRQ) at days 14, 28, 56 and 180 post start of treatment
•Physical symptoms as assessed by the Integrated Palliative care Outcome Scale (IPOS) at days 14, 28, 56 and 180 post start of treatment
•Quality of Life (QoL) as assessed by the EQ-5D-5L and associated VAS at days 14, 28, 56, 180 post start of treatment and Australia-modified Karnofsky Performance Scale (AKPS) at days 14, 28, 56 and 180 post start of treatment
•Anxiety and depression as assessed by the Hospital Anxiety and Depression Scale (HADS) at days 28, 56 and 180 post start of treatment
•Perceived self-efficacy as measured by the Generalized Self-Efficacy Scale (GSES) at day 56 post start of treatment
•The consumption of opioids as measured by opioid medication usage at days 7, 14, 28, 56 and 180 post start of treatment
•Healthcare services received, including out of hours care, number of emergency hospital attendances and admissions within 28 and 56 days post start of treatment and in the 3 month period prior to day 180 post start of treatment as measured by the Client Services Receipt Inventory (CSRI)
•Safety as assessed by the occurrence of:
oSAEs, SARs and SUSARs coded according to mild, moderate or severe as reported at days 7, 14, 28 and 56 post start of treatment
oDeaths by day 56 and day 180 post start of treatment
•Toxicity as assessed by adverse reactions (ARs) coded according to mild, moderate or severe as reported at days 7, 14, 28 and 56 post start of treatment
•Tolerability as assessed by the proportion of patients not withdrawing due to adverse reactions
•Baseline demographics and characteristics will be measured to enable prognostic evaluation of those factors most associated with benefit from mirtazapine (benefit as measured by worst breathlessness over the last 24 hours at day 56 post start of treatment. Specifically assessing: age, gender, functional status (as measured by actual functioning using AKPS, mobility using EQ-5D-5L, and ‘poor mobility’ using IPOS), aetiology (COPD / ILD), baseline intensity of breathlessness (as measured by worst breathlessness over the last 24 hours at baseline), anxiety and depression (as measured by HADS), concomitant opioid administration
•Formal and informal care use over the previous period as measured by the Client Services Receipt Inventory (CSRI) at days 28, 56 and 180 post start of treatment, to examine hours of care and (using country specific unit costs) costs of services
•Acceptability of the offered treatment as assessed by the recruitment conversion rate, the number of people withdrawing from treatment, and the number of participants who request mirtazapine from their doctor/clinician after 56 days post start of treatment
•Treatment compliance as measured by the:
oproportion and type of dropouts over 56 days post start of treatment,
oproportion of tablets taken over 56 days post start of treatment,
oproportion of participants who escalate dose at days 14 and 28 post start of treatment,
oOff trial treatment compliance to 180 days post start of treatment];
•Caregiver’s perceived impact on the participant and themselves as measured by:
oWorst and average rating of the participant’s breathlessness over the last 24 hours as assessed by NRS (0=no breathlessness to 10=worst possible breathlessness) at days 28, 56 and 180 post start of treatment;
oCaregiver assessment of the participant’s number and duration of episodes of breathlessness over the last 24 hours;
oInformal care hours as measured by the Client Services Receipt Inventory (CSRI) at days 28, 56 and 180 post start of treatment;
oCaregiver self-reported burden as measured by the Zarit Burden interview at days 28, 56 and 180 post start of treatment;
oCaregiver self-reported experiences of caregiving as measured by the Positive Aspects of Caregiving scale (PAC) at days 28, 56 and 180 post start of treatment;
oCaregiver perspectives on participants’ situation as measured by the Integrated Palliative care outcome scale (IPOS) at days 28, 56 and 180 post start of treatment.
oCaregiver overall health and wellbeing as measured by EQ-5D-5L and associated VAS at days 28, 56 and 180 post start of treatment.
oCaregiver perspectives on how participants would rate their own overall health and wellbeing as measured by the proxy EQ-5D-5L and associated VAS at days 28, 56 and 180 post start of treatment.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| All secondary endpoint will de evaluated when all participants have been followed up to completion i.e. 180 days post randomisation. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 8 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| The end of trial is defined as the date of the final data download for final analysis. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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